A rapid synthesis of 2-alkynylindoles and 2-alkynylbenzofurans

Article abstract of DOI:10.1016/j.tet.2008.05.059

An expeditious synthesis of 2-alkynylindoles and 2-alkynylbenzofuran derivatives has been devised starting from easily available ortho-substituted aryl diynes.

Full text of DOI:10.1016/j.tet.2008.05.059

Tetrahedron 64 (2008) 7301–7306
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A rapid synthesis of 2-alkynylindoles and 2-alkynylbenzofurans
*
Vito Fiandanese , Daniela Bottalico, Giuseppe Marchese, Angela Punzi
`
Dipartimento di Chimica, Universita di Bari, via Orabona 4, 70126 Bari, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 March 2008
Received in revised form 24 April 2008
Accepted 15 May 2008
An expeditious synthesis of 2-alkynylindoles and 2-alkynylbenzofuran derivatives has been devised
starting from easily available ortho-substituted aryl diynes.
Ó 2008 Elsevier Ltd. All rights reserved.
Available online 18 May 2008
1. Introduction
and successful application of our methodology led to a straightfor-
ward synthesis of a variety of bis-indolyl and bis-benzofuran de-
The indole nucleus is a prominent structural unit frequently
found in numerous natural products and pharmaceutically active
compounds.1 Various 2-substituted indoles exhibit interesting
pharmacological properties2 such as antithrombotic,2a anticancer2b
and histamine H3 receptor antagonist.2c Consequently, the de-
velopment of efficient methodologies for the synthesis of these
compounds continues to be an active area of research.3,4 Among the
various synthetic strategies, one of the modern approaches for
forming indoles is based upon the Pd-catalyzed ring closure of
functionalised 2-alkynylaniline derivatives.3b,c Moreover, many
kind of reagents have been reported for indole synthesis, such as
the rhodium-catalyzed cycloisomerization of 2-alkynylanilines,4b
the indole ring synthesis from 2-ethynylaniline derivatives cata-
lyzed by Cu(II) salts4m and the synthesis of polyfunctional indoles
mediated by caesium and potassium bases.4p
The benzofuran ring can be found as a key structural unit in
many natural products and biologically active compounds,5 and
therefore a growing interest has been devoted towards the syn-
thesis of benzofuran derivatives, because of their activities as
antitumour agents,6 as ligands of the adenosine A1 receptors,7 and
as inhibitors of 5-lipoxygenase.8 A number of efficient and selective
methods have been developed for their synthesis,9 but generally
benzofurans are prepared by either palladium-catalyzed one-pot
annulations of ortho-hydroxy aryl halides with alkynes3c,9a,c,g,10 or
the metal-4b,11 or base-mediated cyclization of ortho-alkynyl
phenols.4p,12
rivatives. We now report a simple method to prepare both indole
and benzofuran scaffolds bearing an alkyne at the 2-position and
show the possibility of an expeditious synthesis of various func-
tionalized 2-alkynylindoles and 2-alkynylbenzofurans starting
from easily available ortho-substituted aryl diynes.18
2. Results and discussion
Relatively to the synthesis of 2-alkynylindole derivatives, as
depicted in Scheme 1, our approach was based upon coupling re-
actions between the 2-(4-trimethylsilyl-1,3-butadiyn-1-yl)aniline
118 and various aryl halides and subsequent annulation of the
resulting products with bases. Then, we subjected the mono-
silylated compound 1 to a direct cross-coupling reaction with
different aryl iodides 3, according to our previously reported pro-
cedure,13 in the presence of catalytic amounts of Pd(PPh3)4 and
AgCl. Various aryl iodides 3 were used, bicyclic a-iodonaphtalene
(entry 3), ortho-substituted (entry 5) and para-substituted (entries
2, 4 and 6) aryl iodides, and all the functionalized 1,3-butadiynes 4
were obtained in high yields (73–82%) (Table 1). Then, in order to
demonstrate the versatility of compounds 4 as useful precursors of
functionalized indole systems, we started to investigate the cycli-
zation reaction conditions. We found that the substituted buta-
diynylaniline derivatives
4
were efficiently converted into
We have recently reported successfully the applications of our
methodology,13 which led to the synthesis of a variety of un-
symmetrically substituted conjugated diynes, to the preparation of
a series of natural diacetylenic compounds,14–16 and of naturally
occurring polyacetylenes.17 Moreover, more recently,18 a further
Ar-X
3
SiMe3
Ar
Pd(0)
1
NH2
4
NH2
KH
NMP, r.t.
Ar
N
H
5
* Corresponding author. Tel./fax: þ39 0805442075.
E-mail address: fianda@chimica.uniba.it (V. Fiandanese).
Scheme 1. Conversion of compound 1 into 2-alkynylindole derivatives 5.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.059

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V. Fiandanese et al. / Tetrahedron 64 (2008) 7301–7306
Table 1
Synthesis of 2-alkynylindoles 5 via Scheme 1
Entry
1
Ar–X 3
Coupling products 4a
Yieldsb (%)
80
2-Alkynylindoles 5c
Yieldsb (%)
64
I
I
N
NH2
H
3a
4a
5a
CH3
CH3
2
79
50
N
H
NH2
H3C
4b
5b
3b
I
3
4
81
73
50
N
H
NH2
4c
5c
3c
I
NH2
NH2
68d
N
H
NH2
4d
5d
H2N
3d
I
N
5
76
82
64
63
H
OCH3
CH3O
5e
NH2
CH3O
4e
3e
I
OCH3
OCH3
N
H
6
NH2
CH3O
4f
5f
3f
a
All reactions were carried out in DMF at 40 ꢁC for 12 h, according to a general procedure.
Yields of purified isolated products.
Unless otherwise indicated, all reactions were carried out in NMP at room temperature for 1 h, according to a general procedure.
Reaction performed at 55 ꢁC for 20 h.
b
c
d
2-alkynylindole derivatives (50–68% yields) by means of KH in N-
methylpyrrolidinone (NMP).4p It is noteworthy that the results have
not been optimized (e.g., type of base for the cyclization) since we
intended only to demonstrate the validity of our approach.
With regards to the synthesis of 2-alkynylbenzofuran de-
rivatives we found that, by employing the same approach, (Scheme
2), based upon coupling and cyclization reactions, these com-
pounds were obtained easily in one step by a tandem coupling/
cyclization reaction. Indeed, starting from 2,18 2-(4-trimethylsilyl-
1,3-butadiyn-1-yl)-tert-butyldimethylsilylphenol, when we sub-
jected this compound to the coupling reaction with various aryl
halides, the heterocyclic 2-alkynylbenzofuran derivatives 6 were
directly obtained in fair to good yields (40–85%). The overall results
are reported in Table 2. Various para-substituted (entries 2, 4, 5 and
6) aryl halides were used and also heterocyclic halides (entries 7
and 8) and a vinyl bromide (entry 9) were used.
readily accessible starting materials. A special advantage of our
strategy is represented by the possibility of preparing different
heterocyclic systems starting from the same compound and fol-
lowing the same reaction sequence. Moreover, in principle, we wish
to underline that with this procedure it is sufficient to choose dif-
ferent aryl halides to perform with success, and in two or one step,
the synthesis of various substituted 2-alkynylindoles and 2-alky-
nylbenzofurans, without the necessity of the preparation of dif-
ferent and not always available terminal alkynes, according to the
general procedure reported in the literature. Therefore, we believe
that this method represents one of the shortest and efficient routes
for the access to this important class of compounds that compares
favourably also with an alternative recent methodology.19 Further
investigations towards the synthesis of more complex and elabo-
rate molecules, having the indole and the benzofuran skeleton as
a core framework, are currently in progress.
3. Experimental
3.1. General
ArX
3
SiMe3
Ar
Pd(0)
O
OTBDMS
2
6
Macherey–Nagel silica gel (60, particle size 0.040–0.063 mm)
for column chromatography and Macherey–Nagel aluminium
sheets with silica gel 60 F254 for TLC were used. GC analysis was
performed on a Varian 3900 gas chromatograph equipped with
a Supelco capillary column (SLBÔ-5ms, 30 mꢀ0.25 mm id). GC/
Scheme 2. Conversion of compound 2 into 2-alkynylbenzofuran derivatives 6.
In summary, we have developed a convenient and rapid syn-
thesis of 2-alkynylindoles and 2-alkynylbenzofurans employing
mass-spectrometric analysis was performed on
a Shimadzu

V. Fiandanese et al. / Tetrahedron 64 (2008) 7301–7306
7303
Table 2
3.2. General procedure for the synthesis of compounds 4
Synthesis of 2-alkynylbenzofurans 6 via Scheme 2
2-Alkynylbenzofurans 6a
Yieldsb (%)
65
To a solution (0.4 N) of aryl iodide 3 (1.0 equiv) in anhydrous
DMF, at room temperature under nitrogen, were successively
added Pd(PPh3)4 (0.05 equiv), AgCl (0.2 equiv) and K2CO3
(8.0 equiv). The resulting mixture was stirred for 5 min, then MeOH
(8.0 equiv) was added followed by a solution (0.4 N) of 2-(4-
trimethylsilyl-1,3-butadiyn-1-yl)aniline 1 (1.0 equiv) in anhydrous
DMF. The reaction mixture was warmed to 40 ꢁC and stirred at the
same temperature for 12 h, then quenched with aqueous NH4Cl and
extracted with ethyl acetate. The organic extracts were washed
with water, dried over anhydrous Na2SO4 and concentrated under
vacuum. The residue was purified by column chromatography on
silica gel.
Entry
1
Halides 3
I
O
3a
6a
I
CH3
2
3
52
53
O
6b
H3C
3b
I
O
3.2.1. 2-(4-Phenylbuta-1,3-diyn-1-yl)aniline (4a)
6c
Product 4a was prepared from 1 (0.200 g, 0.94 mmol) and
iodobenzene 3a (0.192 g, 0.94 mmol) in accordance with general
procedure. Purification by column chromatography (silica gel, 20%
ethyl acetate/petroleum ether) afforded 0.163 g of product 4a (80%
yield) as a yellow-brown solid (mp¼73–75 ꢁC). [Found: C, 88.52; H,
5.15; N, 6.50. C16H11N requires C, 88.45; H, 5.10; N, 6.45%.] nmax (KBr)
3466, 3376, 2205, 2137, 1607, 1450, 1307, 1254, 1157, 1069, 1022, 913,
750, 688; dH (500 MHz, CDCl3) 7.55–7.50 (m, 2H), 7.38–7.30 (m, 4H),
7.15 (ddd, J¼8.4, 7.4, 1.5 Hz, 1H), 6.71–6.65 (m, 2H), 4.31 (br s, 2H);
dC (125.7 MHz, CDCl3) 149.5, 133.0, 132.3, 130.6, 129.1, 128.4, 121.8,
117.9, 114.3, 106.0, 82.7, 79.0, 78.6, 73.9; MS m/z 217 (Mþ, 100),
216 (44), 190 (10), 189 (25), 163 (5), 150 (3), 139 (3), 115 (3), 114 (4),
113 (4), 109 (25), 96 (10), 94 (26), 89 (10), 83 (8), 81 (10), 63 (7),
51 (7%).
3c
I
NH2
4
40
O
6d
H2N
3d
I
OCH3
5
6
55
70
O
6f
CH3O
3f
I
NO2
3.2.2. 2-[4-(4-Methylphenyl)buta-1,3-diyn-1-yl]aniline (4b)
Product 4b was prepared from 1 (0.300 g, 1.41 mmol) and 4-
iodotoluene 3b (0.307 g, 1.41 mmol) in accordance with general
procedure. The residue was purified by column chromatography
(silica gel, 20% ethyl acetate/petroleum ether) leading to 0.257 g
(79% yield) of compound 4b as an orange solid (mp¼107–109 ꢁC).
[Found: C, 88.32; H, 5.63; N, 6.00. C17H13N requires C, 88.28; H,
5.67; N, 6.06%.] nmax (KBr) 3461, 3370, 2205, 2132, 1609, 1457, 1312,
1253, 1156, 1028, 810, 748, 522; dH (500 MHz, CDCl3) 7.42 (d,
J¼8.1 Hz, 2H), 7.34 (dd, J¼8.0, 1.4 Hz, 1H), 7.19–7.10 (m, 3H), 6.73–
6.62 (m, 2H), 4.30 (br s, 2H), 2.36 (s, 3H); dC (125.7 MHz, CDCl3)
149.5, 139.5, 133.0, 132.3, 130.5, 129.2, 118.7, 117.9, 114.3, 106.2, 83.0,
79.1, 78.2, 73.3, 21.6; MS m/z 231 (Mþ, 100), 230 (38), 229 (10), 228
(16), 216 (14), 202 (20), 189 (7), 176 (4), 163 (4), 151 (4), 139 (4), 115
(62), 114 (39), 102 (28), 101 (38), 100 (13), 89 (20), 88 (24), 76 (11),
75 (11), 63 (15), 51 (12%).
O
6g
O2N
3g
I
7
8
73
85
S
S
O
6h
3h
I
N
O
N
6i
3i
Me3Si
3j
SiMe3
Br
9
78
O
3.2.3. 2-(4-Naphthalen-1-ylbuta-1,3-diyn-1-yl)aniline (4c)
Compound 4c was prepared from 1 (0.200 g, 0.94 mmol) and 1-
iodonaphthalene 3c (0.239 g, 0.94 mmol) in accordance with gen-
eral procedure. Purification by column chromatography (silica gel,
20% ethyl acetate/petroleum ether) afforded compound 4c (0.251 g,
81% yield) as a yellow-brown solid (mp¼107–109 ꢁC). [Found: C,
89.75; H, 4.85; N, 5.30. C20H13N requires C, 89.86; H, 4.90; N, 5.24%.]
nmax (KBr) 3447, 3360, 2201, 2132, 1610, 1488, 1450, 1311, 1252, 1157,
797, 769, 746; dH (500 MHz, CDCl3) 8.37 (d, J¼8.4 Hz, 1H), 7.86
(d, J¼8.4 Hz, 2H), 7.78 (dd, J¼7.1, 0.7 Hz, 1H), 7.63–7.57 (m, 1H),
7.56–7.51 (m, 1H), 7.43 (dd, J¼8.2, 7.2 Hz, 1H), 7.40 (dd, J¼7.9, 1.5 Hz,
1H), 7.20–7.14 (m, 1H), 6.74–6.67 (m, 2H), 4.37 (br s, 2H); dC
(125.7 MHz, CDCl3) 149.6, 133.8, 133.1, 133.0, 131.9, 130.7, 129.7,
128.4, 127.2, 126.7, 126.0, 125.2, 119.5, 118.0, 114.4, 106.1, 81.0, 79.7,
79.2, 78.5; MS m/z 267 (Mþ, 100), 266 (49), 265 (15), 264 (16), 239
(18), 237 (9), 213 (3), 211 (2), 187 (3), 176 (2), 163 (4), 150 (3), 134
(43), 133 (26), 121 (11), 109 (71), 106 (29), 94 (10), 89 (20), 63 (7),
51 (5%).
6j
a
All reactions were carried out in DMF at 40 ꢁC for 1–5 h, according to a general
procedure.
b
Yields of purified isolated products.
GC–MS-QP5000 gas chromatograph–mass spectrometer equipped
with a Supelco capillary column (SLBÔ-5ms, 30 mꢀ0.25 mm id). 1H
NMR spectra were recorded in deuterochloroform or acetone-d6 on
a Bruker AM 500 spectrometer at 500 MHz or on a Varian Inova at
400 MHz. 13C NMR spectra were recorded in deuterochloroform or
acetone-d6 on a Bruker AM 500 spectrometer at 125.7 MHz or on
a Varian Inova at 100.6 MHz. IR spectra were recorded on a Perkin–
Elmer FT-IR Spectrum Bx spectrometer. Melting points (un-
corrected) were determined on a Reichert Microscope. Elemental
analyses were recorded on a Carlo Erba EA 1108 elemental analyzer.
N,N-Dimethylformamide was distilled over molecular sieves and
commercial NMP was used as-supplied.

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V. Fiandanese et al. / Tetrahedron 64 (2008) 7301–7306
3.2.4. 2-[4-(4-Aminophenyl)buta-1,3-diyn-1-yl]aniline (4d)
column chromatography on silica gel (10% ethyl acetate/petroleum
ether) leading to 0.029 g (64% yield) of compound 5a as a pale or-
ange solid (mp¼168–170 ꢁC, lit.19 mp¼161–162 ꢁC). nmax (KBr)
3374, 1592, 1530, 1480, 1440, 1394, 1347, 1303, 1104, 1024, 794, 747,
687, 653, 507; dH (500 MHz, CDCl3) 8.21 (br s, 1H), 7.60 (dd, J¼8.0,
0.8 Hz, 1H), 7.55–7.51 (m, 2H), 7.38–7.30 (m, 4H), 7.23 (ddd, J¼8.0,
7.1,1.0 Hz,1H), 7.12 (ddd, J¼8.0, 7.1,1.0 Hz,1H), 6.84–6.81 (m,1H); dC
(125.7 MHz, CDCl3) 136.2, 131.5, 128.6, 128.5, 127.8, 123.5, 122.6,
120.9,120.5,118.8,110.7,108.8, 92.5, 81.8; MS m/z 217 (Mþ,100), 216
(33), 189 (14), 109 (26), 94 (18), 83 (6), 81 (7), 63 (7), 51 (6%).
Compound 4d was prepared from 1 (0.200 g, 0.94 mmol) and 4-
iodoaniline 3d (0.206 g, 0.94 mmol) in accordance with general
procedure. Purification by column chromatography (silica gel, 50%
ethyl acetate/petroleum ether) gave 4d (0.159 g, 73% yield) as
a yellow-brown solid (mp¼140–143 ꢁC). [Found: C, 82.75; H, 5.29;
N, 12.00. C16H12N2 requires C, 82.73; H, 5.21; N, 12.06%.] nmax (KBr)
3432, 3325, 3204, 2199, 2131, 1594, 1481, 1449, 1301, 1260, 1173,
1155, 1093, 1023, 828, 741, 526; dH (500 MHz, acetone-d6) 7.30–7.22
(m, 3H), 7.12–7.09 (m, 1H), 6.79 (d, J¼8.4 Hz, 1H), 6.68 (d, J¼8.7 Hz,
2H), 6.59 (t, J¼7.5 Hz, 1H), 5.20 (br s, 2H), 5.18 (br s, 2H); dC
(125.7 MHz, acetone-d6) 151.7, 150.8, 134.5, 133.4, 131.1, 117.4, 115.0,
114.8, 108.9, 106.1, 84.9, 79.9, 78.7, 72.3; MS m/z 232 (Mþ, 100), 231
(41), 214 (7), 204 (23), 203 (10), 176 (9), 151 (6), 117 (12), 116 (72),
115 (9), 102 (85), 90 (10), 89 (42), 88 (39), 77 (17), 76 (22), 75 (16),
63 (14), 62 (12), 52 (11), 51 (11), 41 (8%).
3.3.2. 2-[(4-Methylphenyl)ethynyl]-1H-indole (5b)20
Compound 5b was prepared from 4b (0.150 g, 0.65 mmol) in
accordance with general procedure. Purification by column chro-
matography (silica gel, 10% ethyl acetate/petroleum ether) afforded
0.075 g (50% yield) of product 5b as a light brown solid (mp¼186–
188 ꢁC, lit.20 mp¼178–182 ꢁC). nmax (KBr) 3397, 2961, 2923, 2852,
1260, 1099, 1018, 816, 793, 749, 735; dH (500 MHz, acetone-d6)
10.67 (br s, 1H), 7.57 (d, J¼8.1 Hz, 1H), 7.46–7.38 (m, 3H), 7.26–7.15
(m, 3H), 7.06 (t, J¼7.5 Hz, 1H), 6.79 (br s, 1H), 2.34 (s, 3H); dC
(125.7 MHz, acetone-d6) 139.2, 137.2, 131.5, 129.7, 128.3, 123.4,
120.8, 120.3, 120.1, 119.3, 111.4, 108.1, 92.2, 81.9, 20.9; MS m/z 231
(Mþ, 100), 230 (27), 228 (10), 216 (9), 202 (11), 189 (4), 115 (54), 114
(29),102 (21),101 (20), 89 (14), 88 (14), 76 (6), 75 (6), 63 (9), 51 (6%).
3.2.5. 2-[4-(2-Methoxyphenyl)buta-1,3-diyn-1-yl]aniline (4e)
Compound 4e was prepared from 1 (0.200 g, 0.94 mmol) and 2-
iodoanisole 3e (0.220 g, 0.94 mmol) in accordance with general
procedure. The residue was purified by column chromatography
(silica gel, 20% ethyl acetate/petroleum ether) leading to product 4e
(0.177 g, 76% yield) as a yellow-brown solid (mp¼46–48 ꢁC).
[Found: C, 82.65; H, 5.29; N, 5.69. C17H13NO requires C, 82.57; H,
5.30; N, 5.66%.] nmax (CCl4) 3489, 3393, 2958, 2930, 2210, 2137,1614,
1594, 1488, 1458, 1276, 1252, 1159, 1117, 1048, 1027; dH (500 MHz,
CDCl3) 7.47 (dd, J¼7.6, 1.5 Hz, 1H), 7.35–7.29 (m, 2H), 7.13 (ddd,
J¼8.1, 7.4, 1.5 Hz, 1H), 6.91 (td, J¼7.6, 0.9 Hz, 1H), 6.88 (d, J¼8.4 Hz,
1H), 6.69–6.63 (m, 2H), 4.33 (br s, 2H), 3.90 (s, 3H); dC (125.7 MHz,
CDCl3) 161.3, 149.5, 134.4, 133.1, 130.7, 130.5, 120.6,117.9, 114.3, 111.1,
110.7, 106.3, 79.3, 79.2, 79.1, 77.6, 55.8; MS m/z 247 (Mþ, 100), 246
(69), 230 (8), 218 (25), 217 (36), 204 (34), 203 (20), 202 (12), 189 (9),
176 (21), 151 (11), 150 (8), 124 (14), 123 (34), 109 (20), 102 (22), 101
(11), 96 (12), 94 (24), 89 (28), 88 (26), 81 (11), 77 (11), 76 (15), 75
(22), 63 (13), 62 (11), 51 (14%).
3.3.3. 2-(Naphthalen-1-ylethynyl)-1H-indole (5c)
Compound 5c was prepared from 4c (0.150 g, 0.56 mmol) in
accordance with general procedure. Purification by column chro-
matography (silica gel, 10% ethyl acetate/petroleum ether) led to
compound 5c (0.075 g, 50% yield) as a light brown solid (mp¼112–
114 ꢁC). [Found: C, 89.90; H, 4.93; N, 5.20. C20H13N requires C,
89.86; H, 4.90; N, 5.24%.] nmax (KBr) 3407, 2197, 1349,1307, 796, 768,
750, 651, 486; dH (500 MHz, CDCl3) 8.40 (d, J¼8.4 Hz, 1H), 8.33 (br s,
1H), 7.86 (t, J¼8.0 Hz, 2H), 7.76 (dd, J¼7.2, 1.0 Hz, 1H), 7.65–7.58 (m,
2H), 7.56–7.52 (m, 1H), 7.46 (dd, J¼8.1, 7.1 Hz, 1H), 7.36 (br d,
J¼8.1 Hz, 1H), 7.25 (ddd, J¼8.1, 7.1, 1.0 Hz, 1H), 7.15 (ddd, J¼7.9, 7.1,
0.8 Hz, 1H), 6.95–6.92 (m, 1H); dC (125.7 MHz, CDCl3) 136.3, 133.2,
133.1, 130.4, 129.1, 128.4, 127.9, 126.9, 126.6, 126.1, 125.3, 123.6,
120.9, 120.6, 120.2, 118.9, 110.8, 109.1, 90.8, 86.5; MS m/z 267 (Mþ,
100), 266 (34), 265 (10), 264 (13), 239 (13), 163 (3), 150 (3), 134 (41),
133 (18), 119 (40), 106 (18), 89 (11), 63 (6), 51 (4%).
3.2.6. 2-[4-(4-Methoxyphenyl)buta-1,3-diyn-1-yl]aniline (4f)
Compound 4f was prepared from 1 (0.200 g, 0.94 mmol) and 4-
iodoanisole 3f (0.220 g, 0.94 mmol) in accordance with general
procedure. Purification by column chromatography (silica gel, 30%
ethyl ether/petroleum ether) gave 0.190 g (82% yield) of compound
4f as a yellow-brown solid (mp¼105–107 ꢁC). [Found: C, 82.60; H,
5.29; N, 5.61. C17H13NO requires C, 82.57; H, 5.30; N, 5.66%.] nmax
(KBr) 3454, 3364, 2922, 2208, 2132, 1616, 1596, 1507, 1485, 1458,
1450, 1288, 1244, 1171, 1023, 833, 757, 535; dH (500 MHz, CDCl3)
7.46 (d, J¼8.9 Hz, 2H), 7.33 (dd, J¼8.2, 1.7 Hz, 1H), 7.16–7.10 (m, 1H),
6.85 (d, J¼8.9 Hz, 2H), 6.70–6.65 (m, 2H), 4.30 (br s, 2H), 3.80 (s,
3H); dC (125.7 MHz, CDCl3) 160.3, 149.5, 134.0, 133.0, 130.5, 117.9,
114.3, 114.1, 113.7, 106.3, 82.9, 79.2, 78.0, 72.7, 55.3; MS m/z 247 (Mþ,
100), 233 (19), 232 (99), 204 (43), 203 (22), 176 (20), 151 (11), 150
(8), 124 (31), 108 (13), 102 (26), 95 (13), 89 (23), 88 (23), 75 (17), 63
(9), 62 (8), 51 (9%).
3.3.4. 4-(1H-Indol-2-ylethynyl)aniline (5d)
KH (0.070 g, 1.72 mmol) was dissolved in NMP (2.1 mL) under
nitrogen at room temperature, then a solution of 4d (0.100 g,
0.43 mmol) in NMP (2.2 mL) was added dropwise and the mixture
was warmed to 55 ꢁC and stirred for 20 h. The reaction was
quenched with water (20 mL), extracted with ethyl acetate
(3ꢀ20 mL), dried over Na2SO4 and concentrated under vacuum.
Purification by column chromatography (silica gel, 50% ethyl ace-
tate/petroleum ether) led to compound 5d (0.068 g, 68% yield) as
a yellow solid (mp¼205–208 ꢁC). [Found: C, 82.80; H, 5.23; N,
12.00. C16H12N2 requires C, 82.73; H, 5.21; N, 12.06%.] nmax (KBr)
3447, 3386, 3359, 3314, 2201, 1603, 1500, 1296, 1263, 1173, 831, 801,
795, 740, 526; dH (400 MHz, acetone-d6) 10.57 (br s, 1H), 7.53 (d,
J¼7.9 Hz, 1H), 7.38 (d, J¼8.2 Hz, 1H), 7.25 (d, J¼8.4 Hz, 2H), 7.15 (t,
J¼7.6 Hz, 1H), 7.03 (t, J¼7.5 Hz, 1H), 6.73–6.63 (m, 3H), 5.11 (br s,
2H); dC (100.6 MHz, acetone-d6) 149.6, 136.9, 132.8, 128.3, 122.7,
120.4, 120.1, 120.0, 114.2, 111.1, 109.8, 106.9, 93.3, 79.5; MS m/z 232
(Mþ, 100), 231 (27), 214 (4), 204 (13), 177 (4), 176 (6), 151 (4), 117
(11), 116 (57), 102 (43), 89 (19), 88 (18), 77 (9), 76 (9), 63 (7), 51 (5),
44 (5%).
3.3. General procedure for the synthesis of compounds 5
KH (2.4 equiv) was dissolved in NMP (0.5 N) under nitrogen at
room temperature, then a solution (0.2 N) of 2-(4-aryl-1,3-buta-
diyn-1-yl)aniline 4 (1.0 equiv) in NMP was added dropwise and the
mixture was stirred for 1 h at room temperature. The reaction was
quenched with water, extracted with ethyl acetate, dried over
Na2SO4 and concentrated under vacuum. The crude product was
purified by column chromatography on silica gel.
3.3.1. 2-(Phenylethynyl)-1H-indole (5a)18–20
3.3.5. 2-[(2-Methoxyphenyl)ethynyl]-1H-indole (5e)
Product 5a was prepared from 4a (0.046 g, 0.21 mmol) in ac-
cordance with general procedure. The residue was purified by
Compound 5e was prepared from 4e (0.101 g, 0.41 mmol) in
accordance with general procedure. The residue was purified by

V. Fiandanese et al. / Tetrahedron 64 (2008) 7301–7306
7305
column chromatography (silica gel, 10% ethyl acetate/petroleum
ether) leading to 0.065 g (64% yield) of compound 5e as a light
brown solid (mp¼105–107 ꢁC). [Found: C, 82.65; H, 5.27; N, 5.61.
requires C, 87.90; H, 5.21%.] nmax (KBr) 2206, 1562, 1447, 1256, 1164,
1145, 1098, 945, 816, 806, 748, 740, 524; dH (400 MHz, CDCl3) 7.48
(br d, J¼7.7 Hz, 1H), 7.39 (d, J¼8.0 Hz, 3H), 7.26–7.17 (m, 1H), 7.16–
7.13 (m, 1H), 7.09 (d, J¼8.0 Hz, 2H), 6.90 (br s, 1H), 2.29 (s, 3H); dC
(100.6 MHz, CDCl3) 155.1, 139.7, 139.2, 131.8, 129.5, 128.0, 125.7,
123.5, 121.3, 118.9, 111.5, 111.4, 95.5, 79.3, 21.9; MS m/z 232 (Mþ,
100), 231 (26), 202 (22), 189 (7), 176 (3), 163 (3), 139 (3), 116 (24),
101 (29), 89 (7), 88 (12), 76 (7), 63 (7), 51 (4%).
C
17H13NO requires C, 82.57; H, 5.30; N, 5.66%.] nmax (KBr) 3385,
2925, 2207, 1482, 1458, 1353, 1255, 1234, 1159, 1101, 1019, 797, 756,
750, 736, 651, 504. dH (400 MHz, CDCl3) 8.33 (br s, 1H), 7.58 (d,
J¼7.9 Hz, 1H), 7.50 (d, J¼7.4 Hz, 1H), 7.35–7.27 (m, 2H), 7.21
(t, J¼7.6 Hz, 1H), 7.10 (t, J¼7.4 Hz, 1H), 6.95 (t, J¼7.6 Hz, 1H), 6.90 (d,
J¼8.4 Hz, 1H), 6.84 (br s, 1H), 3.91 (s, 3H); dC (100.6 MHz, CDCl3)
160.1,136.4,133.6,130.3,128.1,123.6,121.0,120.8,120.6,119.3,112.0,
111.0, 110.9, 108.9, 89.2, 86.0, 56.0; MS m/z 247 (Mþ, 100), 246 (80),
230 (8), 218 (18), 217 (17), 204 (30), 203 (14), 176 (13), 151 (8), 123
(56), 109 (21), 102 (39), 96 (20), 94 (23), 89 (33), 88 (26), 83 (16), 76
(11), 75 (18), 63 (11), 57 (17), 55 (13), 51 (10), 43 (17), 41 (11%).
3.4.3. 2-(Naphthalen-1-ylethynyl)-1-benzofuran (6c)
Compound 6c was prepared from 2 (0.302 g, 0.92 mmol) and 1-
iodonaphtalene 3c (0.234 g, 0.92 mmol) in accordance with general
procedure. Purification by column chromatography (silica gel, 5%
ethyl acetate/petroleum ether) afforded compound 6c (0.131 g, 53%
yield) as a pale yellow solid (mp¼108–110 ꢁC after crystallization
with hexane). [Found: C, 89.50; H, 4.58. C20H12O requires C, 89.53;
H, 4.51%.] nmax (KBr) 2207, 1588, 1447, 1299, 1253, 1181, 1162, 1147,
1139, 1010, 941, 799, 773, 750, 453. dH (400 MHz, CDCl3) 8.46 (d,
J¼8.3 Hz,1H), 7.88 (d, J¼8.1 Hz, 2H), 7.83 (d, J¼6.5 Hz,1H), 7.70–7.53
(m, 4H), 7.48 (t, J¼8.0 Hz, 1H), 7.43–7.33 (m, 1H), 7.29 (t, J¼7.2 Hz,
1H), 7.12 (br s, 1H); dC (100.6 MHz, CDCl3) 155.0, 138.8, 133.1, 133.0,
130.8, 129.6, 128.4, 127.8, 127.1, 126.6, 126.0, 125.6, 125.2,
123.3, 121.2, 119.4, 111.7, 111.2, 93.4, 84.4; MS m/z 268 (Mþ, 100),
239 (40), 237 (17), 134 (34), 119 (64), 106 (24), 94 (10), 80 (4), 63 (4),
51 (3%).
3.3.6. 2-[(4-Methoxyphenyl)ethynyl]-1H-indole (5f)20
Compound 5f was prepared from 4f (0.101 g, 0.41 mmol) in
accordance with general procedure. Purification by column chro-
matography (silica gel, 10% ethyl acetate/petroleum ether) afforded
0.064 g of compound 5f (63% yield) as a light brown solid
(mp¼170–172 ꢁC, lit.20 mp¼163–165 ꢁC). nmax (KBr) 3416, 2925,
1601,1499, 1302, 1288, 1246, 1027, 836, 823, 798, 750, 739, 650, 535,
482; dH (500 MHz, CDCl3) 8.2 (br s, 1H), 7.59 (d, J¼7.9 Hz, 1H), 7.48
(d, J¼8.9 Hz, 2H), 7.31 (d, J¼8.4 Hz, 1H), 7.22 (t, J¼8.1 Hz, 1H), 7.12 (t,
J¼8.1 Hz, 1H), 6.89 (d, J¼8.9 Hz, 2H), 6.81–6.78 (m, 1H), 3.82 (s, 3H);
dC (125.7 MHz, CDCl3) 159.9, 136.1, 133.0, 127.9, 123.3, 120.7, 120.4,
119.2, 114.6, 114.1, 110.6, 108.3, 92.5, 80.4, 55.3; MS m/z 247 (Mþ,
100), 233 (13), 232 (60), 204 (21), 203 (13), 176 (10), 151 (6),
124 (40), 108 (12), 102 (13), 95 (11), 89 (15), 88 (14), 75 (11), 63 (6),
51 (6%).
3.4.4. 4-(1-Benzofuran-2-ylethynyl)aniline (6d)
Compound 6d was prepared from 2 (0.302 g, 0.92 mmol) and 4-
iodoaniline 3d (0.202 g, 0.92 mmol) in accordance with general
procedure. Column chromatography (silica gel, 50% ethyl acetate/
petroleum ether) followed by extraction with boiling hexane
afforded product 6d (0.086 g, 40% yield) as an orange solid
(mp¼125–128 ꢁC). [Found: C, 82.31; H, 4.80; N, 6.05. C16H11NO
requires C, 82.38; H, 4.75%; N, 6.00%.] nmax (KBr) 3473, 3381, 2197,
1617, 1601, 1569, 1506, 1471, 1447, 1284, 1257, 1095, 1018, 939, 805,
747, 526; dH (400 MHz, CDCl3) 7.54 (d, J¼7.1 Hz, 1H), 7.45 (d,
J¼8.2 Hz, 1H), 7.37 (d, J¼8.5 Hz, 2H), 7.34–7.26 (m, 1H), 7.25–7.19
(m,1H), 6.92 (br s, 1H), 6.62 (d, J¼8.5 Hz, 2H); dC (100.6 MHz, CDCl3)
154.7, 147.4, 139.4, 133.2, 127.9, 125.1, 123.1, 120.9, 114.6, 111.1, 110.8,
110.4, 96.0, 77.7; MS m/z 233 (Mþ, 100), 204 (14), 117 (26), 102 (22),
89 (10), 88 (12), 77 (6), 76 (8), 75 (7), 63 (7), 51 (6%).
3.4. General procedure for the synthesis of compounds 6
To a solution (0.4 N) of halides 3 (1.0 equiv) in anhydrous DMF,
at room temperature under nitrogen, were successively added
Pd(PPh3)4 (0.05 equiv), AgCl (0.2 equiv) and K2CO3 (8.0 equiv). The
resulting mixture was stirred for 5 min, then MeOH (8.0 equiv) was
added followed by a solution (0.4 N) of 2-(4-trimethylsilyl-1,3-
butadiyn-1-yl)-tert-butyldimethylsilylphenol 218 (1.0 equiv) in an-
hydrous DMF. The reaction mixture was warmed to 40 ꢁC and
stirred at the same temperature for 1–5 h then quenched with
aqueous NH4Cl and extracted with ethyl acetate. The organic ex-
tracts were washed with water, dried over anhydrous Na2SO4 and
concentrated under vacuum. The residue was purified by column
chromatography on silica gel.
3.4.5. 2-[(4-Methoxyphenyl)ethynyl]-1-benzofuran (6f)
Compound 6f was prepared from 2 (0.200 g, 0.61 mmol) and 4-
iodoanisole 3f (0.143 g, 0.61 mmol) in accordance with general
procedure. Purification by column chromatography (silica gel, 10%
ethyl acetate/petroleum ether) afforded 0.083 g of compound 6f
(55% yield) as a yellow solid (mp¼101–102 ꢁC after crystallization
with hexane). [Found: C, 82.30; H, 4.93. C17H12O2 requires C, 82.24;
H, 4.87%.] nmax (KBr) 2923, 2850, 2207, 1566, 1498, 1471, 1447, 1281,
1243, 1163, 1143, 1097, 1019, 945, 930, 837, 809, 750, 742, 722, 539;
dH (400 MHz, CDCl3) 7.58–7.49 (m, 3H), 7.46 (dd, J¼8.3, 0.8 Hz, 1H),
7.32 (ddd, J¼8.3, 7.3,1.3 Hz,1H), 7.28–7.20 (m,1H), 6.95 (d, J¼0.9 Hz,
1H), 6.88 (d, J¼8.9 Hz, 2H), 3.82 (s, 3H); dC (100.6 MHz, CDCl3)
160.3, 154.8, 139.1, 133.2, 127.8, 125.3, 123.2, 121.0, 114.1, 113.8, 111.1,
110.9, 95.2, 78.4, 55.3; MS m/z 248 (Mþ, 100), 233 (56), 205 (25), 176
(23), 151 (14), 124 (38), 109 (4), 102 (4), 94 (13), 88 (20), 75 (13), 63
(8), 62 (7), 51 (7%).
3.4.1. 2-(Phenylethynyl)-1-benzofuran (6a)19
Compound 6a was prepared from 2 (0.200 g, 0.61 mmol) and
iodobenzene 3a (0.124 g, 0.61 mmol) in accordance with general
procedure. Purification by column chromatography (silica gel, pe-
troleum ether) afforded 0.086 g of compound 6a (65% yield) as
a pale yellow solid (mp¼74–75 ꢁC, lit.19 mp¼71–72 ꢁC). nmax (KBr)
2211, 1595, 1563, 1440, 1304, 1256, 1165, 944, 816, 746, 687; dH
(400 MHz, CDCl3) 7.70–7.56 (m, 3H), 7.49 (br d, J¼8.2 Hz, 1H), 7.42–
7.36 (m, 3H), 7.34 (dd, J¼8.2, 1.0 Hz, 1H), 7.30–7.22 (m, 1H), 7.02 (br
s, 1H); dC (100.6 MHz, CDCl3) 154.8, 138.7, 131.6, 129.1, 128.4, 127.7,
125.5, 123.2, 121.8, 121.1, 111.6, 111.2, 95.0, 79.6; MS m/z 218 (Mþ,
100), 189 (44), 163 (8), 109 (22), 94 (44), 81 (11), 63 (8), 51 (5%).
3.4.2. 2-[(4-Methylphenyl)ethynyl]-1-benzofuran (6b)
3.4.6. 2-[(4-Nitrophenyl)ethynyl]-1-benzofuran (6g)
Compound 6b was prepared from 2 (0.302 g, 0.92 mmol) and 4-
iodotoluene 3b (0.201 g, 0.92 mmol) in accordance with general
procedure. The residue was purified by column chromatography on
silica gel (10% ethyl acetate/petroleum ether) affording product 6b
(0.111 g, 52% yield) as a pale yellow solid (mp¼106–108 ꢁC after
Compound 6g was prepared from 2 (0.302 g, 0.92 mmol) and 4-
nitroiodobenzene 3g (0.229 g, 0.92 mmol) in accordance with
general procedure. Column chromatography (silica gel, 40% ethyl
acetate/petroleum ether) followed by extraction with boiling hex-
ane led to compound 6g (0.169 g, 70% yield) as an orange solid
(mp¼229–231 ꢁC). [Found: C, 73.05; H, 3.47; N, 5.30. C16H9NO3
crystallization with hexane). [Found: C, 87.95; H, 5.15. C17H12
O

7306
V. Fiandanese et al. / Tetrahedron 64 (2008) 7301–7306
requires C, 73.00; H, 3.45; N, 5.32%.] nmax (KBr) 2202, 1595, 1516,
1338, 1306, 1166, 1107, 945, 849, 831, 814, 757, 745; dH (400 MHz,
CDCl3) 8.23 (d, J¼8.8 Hz, 2H), 7.70 (d, J¼8.8 Hz, 2H), 7.59 (d,
J¼7.8 Hz, 1H), 7.48 (d, J¼8.4 Hz, 1H), 7.39–7.33 (m, 1H), 7.30–7.23
(m, 1H), 7.10 (br s, 1H); dC (100.6 MHz, CDCl3) 155.2, 147.4, 137.6,
132.2, 128.6, 127.4, 126.3, 123.8, 123.6, 121.5, 113.4, 111.4, 93.1, 84.6;
MS m/z 263 (Mþ,100), 233 (19), 217 (18), 190 (10), 189 (49), 188 (17),
187 (24), 163 (10), 150 (6), 139 (5), 109 (5), 98 (5), 94 (24), 81 (19), 63
(10), 51 (9%).
Acknowledgements
This work was financially supported by the University of Bari.
We thank Dr. Di Molfetta Donata for preliminary experiments.
References and notes
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3.4.7. 2-(Thiophen-2-ylethynyl)-1-benzofuran (6h)
Compound 6h was prepared from 2 (0.200 g, 0.61 mmol) and 2-
iodothiophene 3h (0.128 g, 0.61 mmol) in accordance with general
procedure. Purification by column chromatography (silica gel, pe-
troleum ether) afforded compound 6h (0.100 g, 73% yield) as
a white solid (mp¼69–70 ꢁC after crystallization with hexane).
[Found: C, 75.02; H, 3.58; S, 14.25. C14H8OS requires C, 74.97; H,
3.60; S, 14.30%.] nmax (KBr) 2196, 1445, 1413, 1342, 1270, 1254, 1199,
1161, 1142, 1107, 1090, 1037, 1003, 935, 883, 850, 833, 813, 749, 702;
dH (400 MHz, CDCl3) 7.60–7.50 (m, 1H), 7.48 (dd, J¼8.3, 0.8 Hz,
1H), 7.38 (dd, J¼3.7,1.1 Hz,1H), 7.37–7.31 (m, 2H), 7.28–7.23 (m,1H),
7.03 (dd, J¼5.1, 3.7 Hz, 1H), 7.01 (d, J¼0.9 Hz, 1H); dC (100.6 MHz,
CDCl3) 154.9, 138.4, 133.2, 128.6, 127.6, 127.3, 125.7, 123.3, 121.6,
121.2, 111.8, 111.2, 88.4, 83.2; MS m/z 224 (Mþ, 100), 195 (24), 169
(4),152 (16),151 (9), 126 (4), 112 (21), 97 (16), 76 (11), 63 (10), 51 (4),
45 (9%).
3.4.8. 3-(1-Benzofuran-2-ylethynyl)pyridine (6i)19
Compound 6i was prepared from 2 (0.302 g, 0.92 mmol) and 3-
iodopyridine 3i (0.189 g, 0.92 mmol) in accordance with general
procedure. Purification by column chromatography (silica gel, 30%
ethyl acetate/petroleum ether) afforded 0.171 g (85% yield) of
compound 6i as a yellow solid (mp¼77–78 ꢁC after crystallization
with hexane, lit.19 mp¼75–76 ꢁC). nmax (KBr) 2213,1585, 1560, 1469,
1445, 1405, 1349, 1304, 1256, 1167, 1111, 1021, 1008, 945, 885, 813,
798, 747, 735, 696, 497, 444; dH (400 MHz, CDCl3) 8.74 (br s, 1H),
8.52–8.47 (m, 1H), 7.73 (dt, J¼7.9, 1.9 Hz, 1H), 7.50 (dd, J¼7.8, 0.6 Hz,
1H), 7.40 (dd, J¼8.3, 0.8 Hz, 1H), 7.31–7.24 (m, 1H), 7.22–7.14
(m, 2H), 6.98 (d, J¼0.9 Hz, 1H); dC (100.6 MHz, CDCl3) 154.8, 151.9,
149.1, 138.2, 137.8, 127.3, 125.8, 123.3, 122.9, 121.2, 118.9, 112.3, 111.1,
91.5, 82.7; MS m/z 219 (Mþ, 100), 190 (19), 164 (10), 163 (23), 138
(5), 137 (4), 110 (11), 96 (10), 83 (10), 81 (16), 69 (9), 63 (8), 55 (5),
51 (5%).
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13. Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. Tetrahedron Lett. 2003, 44,
9087–9090.
14. Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. Tetrahedron 2004, 60,
11421–11425.
15. Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. J. Organomet. Chem. 2005,
690, 3004–3008.
16. Fiandanese, V.; Bottalico, D.; Cardellicchio, C.; Marchese, G.; Punzi, A. Tetrahe-
dron 2005, 61, 4551–4556.
17. Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. Tetrahedron 2006, 62,
5126–5132.
3.4.9. 2-[(3E)-4-Trimethylsilylbut-3-en-1-yn-1-yl]-1-
benzofuran (6j)
Compound 6j (0.155 g, 70% yield, yellow oil) was obtained from 2
(0.302 g, 0.92 mmol) and (E)-1-bromo2-trimethylsilylethene 3j
(0.165 g, 0.92 mmol) after purification by column chromatography
(silica gel, petroleum ether). [Found: C, 75.00; H, 6.78. C15H16OSi
requires C, 74.95; H, 6.71%.] nmax (neat) 2955, 2191, 1581, 1448,1249,
1199, 1009, 972, 862, 840, 806, 749, 739; dH (400 MHz, CDCl3)
7.56–7.52 (m, 1H), 7.45 (dd, J¼8.3, 0.8 Hz, 1H), 7.32 (ddd, J¼8.4, 7.2,
1.3 Hz, 1H), 7.23 (ddd, J¼8.3, 7.2, 1.0 Hz, 1H), 6.93 (d, J¼0.9 Hz, 1H),
6.68 (d, J¼19.3 Hz, 1H), 6.20 (d, J¼19.3 Hz, 1H), 0.14 (s, 9H); dC
(100.6 MHz, CDCl3) 154.9,148.1,138.7,127.7,125.5,123.2,121.9,121.1,
111.6,111.2, 95.3, 79.8, ꢂ1.8; MS m/z 240 (Mþ, 42), 226 (13), 225 (64),
200 (18), 199 (100), 165 (13), 147 (12), 135 (5), 115 (5), 105 (12), 100
(25), 85 (10), 73 (12), 63 (7), 59 (20), 53 (8), 45 (34), 43 (26%).
18. Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. Tetrahedron 2008, 64, 53–60.
19. Nagamochi, M.; Fang, Y.-K.; Lautens, M. Org. Lett. 2007, 9, 2955–2958.
´
20. Soley, R.; Albericio, F.; Alvarez, M. Synthesis 2007, 1559–1565.